Project Summary/Abstract Rationale: Chronic lung disease (CLD) is the third leading cause of death in the US. Exacerbations, defined by an increase in respiratory symptoms, are the major driver of morbidity and mortality for the frequently overlapping ?obstructive? CLD phenotypes of chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis and asthma. An improved understanding of modifiable risk factors for CLD exacerbations is urgently needed, and ? as demonstrated by advances in cardiovascular research ? a focus on clinical events may support advances in primary prevention of CLD, a priority for the NHBLI Lung Division. To date, options for risk stratification with respect to incident CLD and exacerbations remain limited in the general population, as the majority of prior CLD studies have studied exacerbations only in persons with established disease. Candidate: The candidate is a general internist at Columbia University (CU) and doctoral candidate in Epidemiology. Building upon her publication on subclinical emphysema in the general population as an independent predictor of all-cause mortality, she has developed a protocol to define and adjudicate CLD events for epidemiologic/primary prevention studies. She is applying this protocol in a six-cohort consortium, which she is currently building to study novel risk factors for CLD events. Her long-term career goal is to develop an independent, cross-disciplinary research program leveraging respiratory epidemiology, genomics and imaging to identify biological pathways that may be targeted in order to achieve primary and secondary prevention of CLD exacerbations. Career Development: The candidate's short-term objectives are to complete her epidemiology doctoral training and to obtain formal training in genomics, individualized instruction in advanced pulmonary imaging techniques, and apprenticeship in the operations of clinical research, while receiving ongoing multidisciplinary mentorship from internationally-recognized leaders in respiratory epidemiology, genomics, magnetic resonance angiography, and clinical research. Environment: CU has abundant resources to support this application including its NIH-CTSA funded Irving Institute for Clinical Research. Research: The proposed research will test biologically plausible hypotheses on how hypercoagulability may represent a biological target for primary and secondary prevention efforts, while also leveraging resources unique to the candidate and providing relevant and career-stage appropriate training to promote her development into an independent investigator. Rates of pulmonary emboli are substantially increased in CLD and exacerbations; nonetheless, the extent to which hypercoagulability is a cause, an effect, or a correlate of CLD is unknown. A causal role for hypercoagulability in CLD is supported by recent findings suggesting that hypoxemia promotes hypercoagulability, that pulmonary perfusion is altered in COPD and exacerbations, and by pilot work from the PI that is highly supportive of the main aims. Aims 1A and 1B will test whether elevated levels of hemostatic factors independently predict incident CLD and incident exacerbations in a case-cohort study nested in the Multi-Ethnic Study of Atherosclerosis (MESA) and a multi- cohort pooled sample developed by the candidate, using methods enriched by the candidate's doctoral training, and cohorts with which she has gained considerable experience working. Aim 1C builds upon her prior experience in genetic epidemiology and proposed genomics training to examine whether genetically estimated hemostatic factors are associated with incident CLD events and longitudinal decline in lung function in the same pooled sample. Clinical endpoints will be classified according to an innovative adjudication protocol developed and validated by the candidate. Confirmation of Aim 1 hypotheses would provide a novel CLD risk score for risk stratification in the general population as well as a biological target for CLD prevention and treatment with anticoagulants. Aim 2 will examine alterations in pulmonary perfusion as a mechanism by which hypercoagulability and sludging may relate to CLD pathogenesis and exacerbations. In Aim 2A, the candidate will coordinate, supervise and analyze pulmonary magnetic resonance angiography (MRA) images for the measurement of pulmonary microvascular blood flow (PMBF), a measure developed by the Mentor and Advisor, during and six weeks following acute CLD exacerbation for 30 participants that she will recruit from an existing cohort. Completion of Aim 2A will reinforce training activities in pulmonary imaging and clinical research operations, and will test the hypotheses that PMBF is acutely diminished in exacerbations compared to baseline; that these differences will persist at six weeks later; and that these changes in PMBF will be correlated with concurrently measured hemostatic factors. In Aim 2B, the candidate will test if hemostatic factors are associated with change in PMBF over five years of follow-up in stable COPD and emphysema. Results from Aim 1 will provide a risk score to support an R01 application on prevention in existing NHLBI cohorts. Aim 2 will provide pilot data to support an R01 on hemostatic factor and pulmonary MRA phenotyping of exacerbations in a larger cohort, and potentially an application for a Phase 2 clinical trial of anticoagulants in persons at high risk for exacerbation, using PMBF as an intermediate phenotype. Hence, completion of the proposed training and scientific aims would position the PI as a respiratory epidemiologist with a unique level of epidemiology, genomics, and imaging training, one or more clinically relevant R01- funded projects, and a commitment to research in primary and secondary prevention of CLD.